Ligand and metal complex

Abstract

A ligand of Formula (I) is provided: wherein A 4 represents a hydrogen atom, a nitro group, an amino group, a thiocyanato group, or —Z—Y, in which Z is a divalent linking group and Y is a group derived from a biocompatible molecule, with the proviso that when X is methylene, A 4 cannot be a hydrogen atom or a nitro group. A metal complex having the ligand is also provided and is useful as a blood pool contrast agent or a targeting contrast agent.

1. A metal complex, comprising:
 a paramagnetic metal ion; and 
 a ligand of Formula (i) chelated with said paramagnetic metal ion: 
 
       
         
           
           
               
               
           
         
         wherein, in Formula (i), 
         X represents methylene, 1,1-cyclobutylene, 1,1-cyclopentylene, or 1,1-cyclohexylene; 
         A 1 , A 2  and A 3  independently represent a hydrogen atom, a C 1 ˜C 3  alkyl group, a C 1 ˜C 3  phenylalkyl group, a C 1 ˜C 3  methoxyphenylalkyl group, diphenylmethyl or a C 1 ˜C 3  isothiocyanato phenylalkyl; 
         A 4  represents a hydrogen atom, a nitro group, an amino group, a thiocyanato group, or —Z—Y, in which Z is a divalent linking group and Y is a biocompatible molecule, with the proviso that when X is methylene, A 4  cannot be a hydrogen atom or a nitro group; and 
         R 1 , R 2 , R 3 , and R 4  independently represent a hydrogen atom, an amino group, a nitro group or a thiocyanato group. 
       
     
     
       2. The metal complex of  claim 1 , wherein said metal ion is selected from lanthanide series metal ion, Mn 2+ , or Fe 3+ . 
     
     
       3. The metal complex of  claim 2 , wherein said lanthanide series metal ion is Gd 3+ . 
     
     
       4. The metal complex of  claim 1 , wherein A 4  in Formula (i) is —Z—Y, Z is 
       
         
           
           
               
               
           
         
       
       and Y is a targeting peptide sequence. 
     
     
       5. The metal complex of  claim 4 , wherein said targeting peptide sequence is selected from the group consisting of interleukin-11, bombesin, cyclo(Arg-Gly-Asp), and Leu-Ala-Arg-Leu-Leu-Thr. 
     
     
       6. The metal complex of  claim 5 , wherein X is methylene, A 1 , A 2  and A 3  independently represent a hydrogen atom, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom. 
     
     
       7. The metal complex of  claim 1 , wherein X is methylene or 1,1-cyclobutylene. 
     
     
       8. The metal complex of  claim 1 , wherein A 1 , A 2  and A 3  independently represent a hydrogen atom, methyl, benzyl, methoxyphenylmethyl, diphenylmethyl or isothiocyanato phenylmethyl. 
     
     
       9. The metal complex of  claim 1 , wherein X is methylene, A 1 , A 2  and A 3  independently represent a hydrogen atom, A 4  is a thiocyanato group, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom. 
     
     
       10. The metal complex of  claim 1 , wherein X is 1,1-cyclobutylene, A 1 , A 2 , A 3  and A 4  independently represent a hydrogen atom, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom. 
     
     
       11. A ligand of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein, in Formula (I),
 X represents methylene, 1,1-cyclobutylene, 1,1-cyclopentylene, or 1,1-cyclohexylene; 
 A 1 , A 2  and A 3  independently represent a hydrogen atom, a C 1 ˜C 3  alkyl group, a C 1 ˜C 3  phenylalkyl group, a C 1 ˜C 3  methoxyphenylalkyl group, diphenylmethyl or a C 1 ˜C 3  isothiocyanato phenylalkyl; 
 A 4  represents a hydrogen atom, a nitro group, an amino group, a thiocyanato group, or —Z—Y, in which Z is a divalent linking group and Y is a biocompatible molecule, with the proviso that when X is methylene, A 4  cannot be a hydrogen atom or a nitro group; and 
 R 1 , R 2 , R 3 , and R 4  independently represent a hydrogen atom, an amino group, a nitro group or a thiocyanato group. 
 
     
     
       12. The ligand of  claim 1 , wherein A 4  is —Z—Y, Z is 
       
         
           
           
               
               
           
         
       
       and Y is a targeting peptide sequence. 
     
     
       13. The ligand of  claim 12 , wherein said targeting peptide sequence is selected from the group consisting of interleukin-11, bombesin, cyclo(Arg-Gly-Asp), and Leu-Ala-Arg-Leu-Leu-Thr. 
     
     
       14. The ligand of  claim 13 , wherein X is methylene, A 1 , A 2  and A 3  independently represent a hydrogen atom, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom. 
     
     
       15. The ligand of  claim 11 , wherein X is methylene or 1,1-cyclobutylene. 
     
     
       16. The ligand of  claim 11 , wherein A 1 , A 2  and A 3  independently represent a hydrogen atom, methyl, benzyl, methoxyphenylmethyl, diphenylmethyl or isothiocyanato phenylmethyl. 
     
     
       17. The ligand of  claim 11 , wherein X is methylene, A 1 , A 2  and A 3  independently represent a hydrogen atom, A 4  is a thiocyanato group, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom. 
     
     
       18. The ligand of  claim 11 , wherein X is 1,1-cyclobutylene, A 1 , A 2 , A 3  and A 4  independently represent a hydrogen atom, and R 1 , R 2 , R 3  and R 4  independently represent a hydrogen atom.